EW-7197, a novel ALK-5 kinase inhibitor, potently inhibits breast to lung metastasis

Ji Yeon Son, So Yeon Park, Sol Ji Kim, Seon Joo Lee, Sang A. Park, Min Jin Kim, Seung Won Kim, Dae Kee Kim, Jeong Seok Nam, Yhun Yhong Sheen

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Advanced tumors produce an excessive amount of transforming growth factor β (TGFβ), which promotes tumor progression at late stages of malignancy. The purpose of this study was to develop anti-TGFβ therapeutics for cancer. We synthesized a novel small-molecule TGFβ receptor I kinase (activin receptor-like kinase 5) inhibitor termed N-[[4-([1,2,4]triazolo[1,5-a] pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl]methyl]-2-fluoroaniline (EW-7197), and we investigated its potential antimetastatic efficacy in mouse mammary tumor virus (MMTV)/c-Neu mice and 4T1 orthotopic-grafted mice. EW-7197 inhibited Smad/TGFβ signaling, cell migration, invasion, and lung metastasis in MMTV/c-Neu mice and 4T1 orthotopic-grafted mice. EW-7197 also inhibited the epithelial-to-mesenchymal transition (EMT) in both TGFβ-treated breast cancer cells and 4T1 orthotopic-grafted mice. Furthermore, EW-7197 enhanced cytotoxic T lymphocyte activity in 4T1 orthotopic-grafted mice and increased the survival time of 4T1-Luc and 4T1 breast tumor-bearing mice. In summary, EW-7197 showed potent in vivo antimetastatic activity, indicating its potential for use as an anticancer therapy.

Original languageEnglish
Pages (from-to)1704-1716
Number of pages13
JournalMolecular Cancer Therapeutics
Volume13
Issue number7
DOIs
StatePublished - Jul 2014

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